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¹ Pharmacological Institute and ² School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; ³ Yung-Shin Pharmaceutical Industry Co., Ltd., and ⁴ Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan

Requests for reprints: Che-Ming Teng, Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Taipei 100, Taiwan. Phone: 886-2-23123456, ext. 8310; Fax: 886-2-23221742. E-mail: cmteng{at}ntumc.org

Although the indazole compound, YC-1, is reported to exert anticancer activities in several cancer cell types, its target and mechanism of action have not been well explored. The objectives of this study were to ascertain whether YC-1 directly induces apoptosis in prostate cancer cells and to explore the mechanism(s) whereby YC-1 causes cell death. Hormone-refractory metastatic human prostate cancer PC-3 cells were selected for this study. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay indicated that YC-1 suppresses growth of PC-3 cells in a concentration-dependent and time-dependent manner. Apoptosis was determined using 4',6-diamidino-2-phenylindole staining, and cell cycle progression was examined by FACScan flow cytometry. YC-1 treatment showed chromatin condensation and increased the percentage of PC-3 cells in the hypodiploid sub-G₀-G₁ phase, indicative of apoptosis. Additionally, exposure to YC-1 was found to induce activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Translocation and activation of nuclear factor-B (NF-B) were determined by immunofluorescent staining and ELISA, respectively. The results showed that YC-1 abolished constitutive nuclear translocation and activation of NF-B/p65. Furthermore, inhibition of inhibitor of B (IB) phosphorylation and accumulation of IB were observed. The antitumor effects of YC-1 were evaluated by measuring the growth of tumor xenografts in YC-1-treated severe combined immunodeficient mice. The volumes of PC-3 tumors produced in severe combined immunodeficient mice were observed to decline significantly after treatment with YC-1 compared with vehicle controls. We concluded that the antitumor effects of YC-1 in PC-3 cells include the induction of apoptosis and the suppression of NF-B activation. Given these unique actions, further investigations of the effects of YC-1 against hormone-refractory prostate cancer are warranted.

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Received 3/28/05; revised 7/ 5/05; accepted 8/17/05.